Inhibitors of HIV integrase (IN) are being developed as potential anti-AIDS drugs. One class of lead structure currently under investigation can be broadly characterized as being of the aryl beta-diketo family. Members of this class have been reported independently to exhibit potent inhibition of HIV integrase in extracellular enzyme assays and to provide good antiviral effects in HIV-infected cells. Through the systematic design and synthesis of a large number of aryl beta-diketo analogues, we have developed novel azido containing aryl beta-diketo variants, which exhibit high IN inhibitory potency in extracellular assays and provide antiviral effects with reduced cytotoxicity in HIV infected cells. In order to elucidate the manner in which these and other inhibitors interact with IN-DNA substrate complexes, chemical and photo-activatable affinity labels have been incorporated into high affinity inhibitors. We have also developed the first members of a novel, new class of pharmacological tool that function as "affinity acetylators" by site-specific acetylation of amino acid residues in the IN enzyme. Mass spectral studies are currently ongoing to elucidate sites of covalent attachment by these agents following incubation with the enzyme. To date, highly successful results have been achieved using newly developed affinity acetylators. In separate studies, collaborative efforts are underway to obtain X ray structures of inhibitors bound to the HIV integrase enzyme. Information obtained from such X-ray structures should provide a starting point for the computer-assisted design of potent new inhibitors.